Apalutamid (2) – Erleada®

• Clinical trials
  • The TITAN trial is a double-blind, randomised Phase III trial comparing apalutamide in combination with ADT against treatment with ADT and a placebo.
  • The GETUG trial is an open-label, randomised controlled trial comparing docetaxel in combination with ADT against ADT alone in patients with metastatic prostate cancer.
  • The CHAARTED trial is an open-label, randomised controlled trial comparing treatment with docetaxel in combination with ADT against ADT alone in patients with metastatic prostate cancer.
  • The STAMPEDE study is a randomised, open-label, multi-arm, multi-stage platform study comparing various systemic active ingredients (INN) (12 arms in total) in advanced or metastatic prostate cancer.

Adult men with metastatic hormone-sensitive prostate cancer (mHSPC)

• mortality
  • As of the data cut-off date of 23 November 2018, 83 patients (approx. 16%) in the intervention arm and 117 patients (approx. 22%) in the comparator arm had died in the TITAN study. The median survival time has not yet been reached in either arm of the TITAN trial.
  • In the relevant patient population of the STAMPEDE trial, 225 patients (approx. 62%) in the intervention arm and 494 patients (approx. 68%) in the control arm had died by the data cut-off date of 13 July 2018. The median survival times are 59.1 months and 43.1 months, respectively.
  • In the adjusted indirect comparison, there is no statistically significant difference between apalutamide in combination with ADT and docetaxel in combination with ADT and prednisolone. An additional benefit of apalutamide in combination with ADT in the mortality category is therefore not proven.
• Morbidity – time to first skeletal-related event
  • In the comparison arms of the two studies, there are markedly different rates of patients with skeletal-related events at all time points.
  • Overall, therefore, it is not assumed that there is sufficient similarity between the two studies in terms of endpoints, meaning that, for the endpoint of skeletal-related events, there are no data available that can be used for an adjusted indirect comparison.
  • An additional benefit of apalutamide in combination with ADT in the morbidity category is therefore not proven.
• Health-related quality of life
  • In the TITAN study, data on health-related quality of life were collected using the FACT-P questionnaire. In the STAMPEDE study, data were collected using the EORTC QLQ-C30. Due to the different measurement instruments used in the studies, it is not possible to carry out an indirect comparison.
  • An additional benefit of apalutamide in combination with ADT in the quality of life category is therefore not proven.
• Side effects
  • Monitoring and bias in the endpoints SAE and severe AEs (CTCAE grade ≥ 3)
  • In the TITAN trial, SAE and severe AEs (CTCAE grade ≥ 3) were monitored for up to 30 days after discontinuation of study medication. During the course of the trial, 34% of patients in the intervention arm and 54% of patients in the control arm discontinued treatment. Consequently, the results for both endpoints in the TITAN trial are subject to a high potential for bias due to the potentially high and, between the treatment arms, differing proportions of patients with incomplete follow-up.
  • In the STAMPEDE study, there are marked differences in the duration of follow-up between the treatment arms for the endpoints SAE and severe AE (CTCAE grade ≥ 3).
  • Regarding the results of the adjusted indirect comparison for SAE and severe AEs (CTCAE grade ≥ 3)
  • For the SAE endpoint, the adjusted indirect comparison shows a statistically significant difference in favour of apalutamide in combination with ADT compared with docetaxel in combination with ADT and prednisolone, with an effect estimate of HR: 0.10; 95% CI: 0.06; 0.17. Given the magnitude of this effect, it is not considered that this advantage for SAE is entirely called into question by potential biases.
  • In contrast, the effect estimate for the indirect comparison regarding the endpoint of severe AEs (CTCAE grade ≥ 3) is not considered to provide sufficient certainty of results, taking into account the aforementioned uncertainties.
  • For the endpoint of therapy discontinuations due to adverse events, data from the TITAN trial are available exclusively for the intervention arm of the indirect comparison. It is therefore not possible to perform an adjusted indirect comparison.
  • In the overall review of the results on side effects, results from the adjusted indirect comparison are available only for the endpoint SAE. Although these show a beneficial effect for apalutamide in combination with ADT, this can only be inferred for the period of the first 6 to 7 months after the start of treatment, given the observation periods in the study arms of the STAMPEDE trial. No conclusions can be drawn regarding the endpoint SAE beyond this period.
  • An additional benefit for apalutamide in combination with ADT cannot therefore be inferred with the necessary certainty in the ‘side effects’ category.
• Overall assessment
  • For the assessment of the additional benefit of apalutamide in combination with ADT for the treatment of adult men with metastatic hormone-sensitive prostate cancer (mHSPC), results are available on mortality, morbidity and side effects compared with the appropriate comparator therapy, docetaxel in combination with ADT and prednisolone.
  • For the endpoint of overall survival, the adjusted indirect comparison shows no statistically significant difference between apalutamide in combination with ADT and docetaxel in combination with ADT and prednisolone. An additional benefit of apalutamide in combination with ADT in the mortality category is therefore not proven.
  • In the morbidity endpoint category, it is not assumed that there is sufficient endpoint-related similarity between the two studies for the endpoint ‘time to first skeletal-related event’; consequently, no data suitable for an adjusted indirect comparison are available.
  • Similarly, no usable data are available for an indirect comparison with regard to health-related quality of life, as different data collection instruments were used in the TITAN and STAMPEDE studies.
  • With regard to side effects, the adjusted indirect comparison allows conclusions to be drawn only for the SAE endpoint. Whilst an effect in favour of apalutamide in combination with ADT is evident here, this can only be inferred for the period of the first 6 to 7 months after the start of treatment. No conclusions can be drawn regarding the SAE endpoint beyond this period. No further results are available for endpoints in the categories of side effects, symptoms or quality of life that could be used to interpret this effect or would support it.
  • In its overall assessment, the G-BA therefore concludes that there is no additional benefit of apalutamide in combination with ADT compared with docetaxel in combination with ADT and prednisolone for the treatment of adult men with metastatic hormone-sensitive prostate cancer (patients with distant metastases (stage M1) and good general health (ECOG/WHO 0 to 1 or Karnofsky Index ≥ 70 %)) is not proven.

Courtesy translation only, please refer to the German original.